Statins for the primary prevention of cardiovascular disease

Re: Statins for the primary prevention of cardiovascular disease

In their paper Ebrahim et al refer to the 2013 Cochrane report as an argument for primary prevention with statins. The fact is that no such trial has succeeded in prolonging the life of the participants and this is also what can be deducted from the meta-analysis by the Cholesterol Treatment Trialists (CTT) Collaboration. From table 3 it is possible to calculate that the chance to be alive after five years for people without vascular disease and whose 5-year risk of a major vascular event is lower than 10% is the same, whether they are on statin treatment or not and whether they have a vascular disease or not.

There is a benefit for people whose risk lies between 10% and 20%, but it is trivial at most. According to the table their chance of being alive after five years without treatment is 89.9%. If they take a statin every day they can increase their chance to 90.7%.

And there are other problems with the statin trials. In the Cochrane meta-analysis of the primary preventive statin from 2009 co-authored by Ebrahim, the authors concluded that “there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease ….. only limited evidence showed primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.” Why have these reservations disappeared from the present analysis?

According to Ebrahim et al. earlier concerns about cancer risk are unfounded. They refer to a meta-analysis of the statin trials, but the authors of this analysis have ignored a serious bias.

In the first simvastatin trials, 4S and HPS, the number of non-melanoma skin cancer was increased. As the differences between the treatment and the control groups were not statistically significant, the increase was attributed to chance. However, if the figures from both trials are calculated together, the difference between the treatment and control groups does become statistically significant (256/12454 vs 208/12459; p<0.028). By unknown reason the number of non-melanoma skin cancers has not been reported after the publication of HPS (1).

The lag time between carcinogenic exposure and the clinical appearance of a cancer depends on its location. Lung cancer, for instance, is not diagnosed until after decades of smoking, whereas non-melanoma skin cancers may be observed much earlier. An increased number of patients with skin cancer in a trial is therefore alarming because this is the first cancer type that we should expect to find under conditions of general carcinogenicity (1).

The reason why meta-analyses of the statin trials do not find an increased risk of other cancer types is not only that non-melanoma cancer is unreported, but also that the trials have been too short. In spite of that some of the trials have reported an increase of cancer. In the PROSPER trial the number was 245/2891 vs. 199/2913 (p=0.02). In the CARE trial it was 12/286 women vs. 1/290 women (p=0.002). In the SEAS trial 39/944 vs. 23/929 (p=0.05)(1).

In a cohort study by Matsuzaki et al. 47 294 hypercholesterolemic Japanese patients on 5-10 mg simvastatin per day were followed for 6 years. At follow-up the number of cancer deaths was more than three times higher in patients whose total cholesterol was <160 mg/dl at follow-up compared with those whose cholesterol was normal or high (P<0.001)(1).

Several case-control studies are in accord. In a study by Iwata et al. 13.3% of patients with lymphoid malignancies had been treated with statins compared with 7.3% of control individuals with non-malignant diseases matched for age and sex (p<0.001). In a retrospective study of 388 men with prostate cancer and 1552 matched controls Chang et al. found an increasing cancer risk with increasing cumulative statin dose (x2 for linear trend 7.23; p=0.007). In a study by Agalliou et al. obese men taking statins had an increased risk of prostate cancer compared with obese non-users (OR = 1.5, 95% CI 1.0–2.2), with a stronger association for long-term use (OR = 1.8, 95% CI 1.1–3.0). In a retrospective analysis by Ritch et al., those on statins among 1261 patients who had undergone radical prostatectomy were more likely to have an elevation of biochemical tests that suggested recurrent cancer (p<0.05), and also a more aggressive cancer type reflected as a higher Gleason sum (p<0.05). Finally, Hoffman et al. found that of 83 patients with bladder cancer, the tumor became more aggressive in 53% of those who took statins, in contrast to only 18% for non-users (p=0.004) (1).

The reason why statin treatment may result in cancer is probably not an effect of the drug, but that low cholesterol predisposes to cancer. Thus, nine cohort studies including more than 140 000 individuals found that cancer was inversely associated with cholesterol measured 10–30 years earlier, and the association persisted after exclusion of cancer cases appearing during the first 4 year (1)